Many key biologics are scheduled to lose their patent by the year 2020, which will provide the opportunity to other biopharmaceutical companies to develop the similar biologics. Biosimilar or similar biologic used has increased in the recent year following the approval of the first biosimilar in early 2000. India is one of the leading manufacturers of similar biologics. India has developed a new guideline in 2012 for the pre- and post-marketing approval of similar biologics.

Keywords:Biosimilars, European Medicines Agency, Food and Drug Administration, similar biologics

Biologics are derived from the natural resources such as human, animal, or microorganism and manufactured by various biotechnology methods such as recombinant deoxyribonucleic acid technology, controlled gene expression, and antibody technology.[1],[2] Biologics have benefitted the patients with rheumatologic diseases, inflammatory bowel disease, malignant conditions, dermatological conditions, and other connective tissue disorders by halting the disease progression, alleviating the symptoms, and improving the quality of life.[3],[4] Biologics are one of the top selling drugs worldwide as well as in the United States but the major drawback of this drug has been its exorbitant cost, which makes it unaffordable and inaccessible to many patients, especially in developing countries where a large number of people are poor and the concept of health insurance is at its nascent stage.[5],[6] But the silver lining is that once the innovator company loses their intellectual property right and patent protection after a stipulated period, it opens the window of opportunities for companies evince an interest in manufacturing similar products, which cost less, and at that time, it is known as biosimilar or similar biologic.[7] Biosimilar is a biologic product, which is very similar to Food and Drug Administration (FDA)-approved biological product known as reference product and has no clinically meaningful differences in term of safety and effectiveness from the reference product.[8] But similar biologics are not exactly identical to reference biologics because of the complex structure, which may be affected by minor alteration in sequences and posttranslational modifications.[9]

Many believe that biosimilars will have a positive impact on the drug pricing. Health-care experts and physicians are optimistic that use of biosimilars may reduce the cost of biologics and eventually lead to better patients’ access to these lifesaving drugs.[10] The biosimilars have huge potential to reduce the overall cost of treatment, which was evident from a study carried out in United States where it was estimated over 10 years biosimilar can save 54 billion US dollar in the United States.[11]

Current Status

Europe was the first in the world to formulate the policy framework for the approval of the biological product.[12] The first biosimilar, Omnitrope (a recombinant human growth was), was approved in Europe by the European Medicines Agency (EMA) in 2006.[13],[14] United States followed this much later when in 2015 it approved filgrastim-sndz, a biosimilar to filgrastim (granulocyte CSF), whereas filgrastim was approved by the USFDA in 1991.[15],[16] But since then, FDA has approved a number of biosimilars for the treatment of cancer and other conditions. The latest one to be approved was pegfilgrastim-jmdb in June 2018 to reduce the risk of infection following myelosuppressive chemotherapy.[17] Now there are multiple biosimilars developed by biopharmaceutical companies and used across the world for wide range of areas such as diabetes, ophthalmology, and respiratory to cancer and connective tissue diseases.[18],[19],[20],[21]

India has a thriving biosimilar ecosystem in comparison to other countries and because of that Indian pharmaceutical companies have risen as the global market leaders in biosimilars. India approved its first biosimilar much before the United States and Europe. The first biosimilar was approved and marketed in India in 2000 for hepatitis B, although no specific guideline was available at that time for the development and marketing of biosimilar in India.[22] Since then several biosimilars were developed and marketed in India by various biopharmaceutical companies.[22] Recently, an Indian biopharmaceutical company got the USFDA’s nod for marketing its novel biologic. Herceptin (active drug is trastuzumab) was the first biologic to be approved by FDA, which is used in certain breast and stomach cancer. This was also the first similar biologics manufactured by an Indian company, which received approval to market in the United States.

Presently, there are more than 100 Indian biopharmaceutical companies, which are engaged in manufacturing and marketing of biosimilar. Biosimilar is called as “similar biologics” by Indian regulatory agencies. No specific guideline was available for “similar biologics,” despite the fact that India was one of the first countries in the world to use it, and approval process of similar biologics is more cumbersome and require more data than other generic drugs. To address the issues and challenges associated with the development of similar biologics, Central Drugs Standard Control Organization (CDSCO) in collaboration with the Department of Biotechnology (DBT) has developed “Guidelines on Similar Biologics; Regulatory Requirements for Marketing Authorization in India” in 2012 and has revised it in 2016.[23],[24],[25] These guidelines address the regulation of manufacturing process as well as quality, safety, and efficacy of similar biologics. It also addresses the pre- and post-marketing regulatory requirements for similar biologics. DBT through Review Committee on Genetic Manipulation is responsible for overseeing the development and preclinical evaluation of biologics. The similar biologics in India are regulated as per Drug and Cosmetic Act (1940), Drug and Cosmetic Rules, 1945, and Rules for Manufacture, Use, Import, Export, and Storage of Hazardous Microorganisms/Genetically Engineered Organisms or Cells, 1989 (rules, 1989) notified under Environmental (Protection) Act,1986.[23] CDSCO has brought some important changes in its earlier guideline, such as earlier it was essential for the reference biologic for which biosimilar is to be developed has to be approved and marketed in India but it has now changed to either India or any other international council for harmonisation countries (i.e., European Union, Japan, United States, Canada, and Switzerland). It also tries to align with other international agencies such as EMA and the World Health Organization. According to Indian guideline, biologics are developed by the sequential approach to show the similarity of the molecular and quality characteristic of a biosimilar with reference products. Another difference between the 2012 guidance and the document issued in 2016 is the emphasis on the post-marketing studies, which CDSCO says are intended “to further reduce the residual risk of the similar biologic,” CDSCO has made it essential for the biopharmaceutical company to conduct a Phase IV study with a minimum of 200 patients within 2 years of getting approval for marketing.[23]

The regulator also added a new section on non-comparative safety and efficacy studies, noting that if a product is found to be similar “in pre-clinical, in vitro characterization having established PK (pharmacokinetic) methods and a PD (pharmacodynamic) marker that is surrogate of efficacy, the residual risk is significantly reduced in the Phase I study if equivalence is demonstrated for both PK and PD. Phase III clinical trials of such a Similar Biologics product may be waived...[and] where considered necessary, an appropriate single arm study in at least 100 evaluable subjects may be carried out in the most sensitive indication to address any residual uncertainty.”

CDSCO also added new information on when a confirmatory clinical safety and efficacy study can be waived, noting: “In case the safety and efficacy study is waived all the indications approved for reference product may be granted based on comparable quality, non‐clinical as well as convincing PK/PD data. Wherever the Phase III trial is waived, the immunogenicity should have been gathered in the PK/PD study and will also need to be generated during post-approval Phase IV study.”

Indian companies are taking multiple steps to involve them in manufacturing and marketing to tap this huge potential. Biosimilars approved and used in India mainly consist of the vaccines, monoclonal antibodies, insulin, and recombinant proteins. India has achieved the distinction of being the second largest supplier of vaccines in the world. Various biosimilars have been approved by India for use in different diseases. Some of the biosimilars approved in India are shown in [Table 1].

Many companies will have their patent expire in the forthcoming year, which will open the window of opportunity for other biopharmaceutical companies to explore the possibility of development of biosimilar products. The global market for the biosimilar is expected to grow by US$10 billion and many companies are anticipated to enter into this lucrative sector.

Although the biosimilar space is still growing and evolving in the United States, India is a significant player in the world in manufacturing and using of biosimilars.[26] Indian biosimilar market was approximately US$300 million in 2015. The domestic sales are close to US$250 million and growing at a compound annual growth rate of 14%. The export of biosimilar or similar biologic from India stands at a staggering US$51 million.[18] India has the potential to become a global player in similar biologics or biosimilars. According to ASSOCHAM-Sathguru report released in 2016, biosimilar presents a US$240-billion global opportunity to Indian biopharmaceutical industry and the domestic market is expected to grow US$40 billion by 2030.[27] Institute of Medical Sciences’ health-care report also envisages a similar opportunity for Indian biopharmaceutical companies associated with manufacturing and marketing of biosimilars.

Conclusion

Biosimilars hold promise to improve patient’s accessibility for many malignant and nonmalignant ailments by reducing the treatment cost. Since the use of the first biosimilar, the development and uses of “biosimilars or similar biologics” have witnessed substantial growth. Every year, regulatory agencies are granting approval of various similar biologics for the treatment of many cancerous and noncancerous diseases. India has firmly established itself as a global player as a maker of similar biologics. It is also a huge market for the similar biologics because of its burgeoning population. Although the potential is high and expectation is huge for India, the challenges are also enormous and daunting to maintain the leadership. To achieve the true potential and continue as a global leader, Indian biopharmaceutical companies need to upgrade their technology and have to improve the manpower skill. For this, they need an enabling environment from the government and regulatory agencies

FDA approves first biosimilar to Neulasta to decrease the risk of infection during cancer treatment, https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm609823.htm [Last accessed on 2018 July 2]

GUIDELINE ON SIMILAR BIOLOGICS: Regulatory Requirements for Marketing Authorization in India,2016, http://www.dbtindia.nic.in/wp-content/uploads/10.-Guidelines-on-Similar-Biologics-2016.pdf [Last accessed on 2018 June 22]